DESCRIPTION (From the applicant's abstract): Spinocerebellar ataxia type 7 (SCA7) is among a group of neurodegenerative disorders caused by an expansion of a CAG triplet encoding a polyglutamine tract within the disease protein. While substantial progress has been made towards understanding the molecular basis of pathogenesis for some SCAs, it is still uncertain the extent to which residues outside of the polyglutamine tract are important for disease. Using a strategy that has proven very effective for elucidating molecular features of SCA1 pathogenesis, the applicants propose to examine the molecular basis of SCA7 pathogenesis. The aims of this application are: To use transgenic mice to examine Purkinje cell pathology induced by mutant ataxin-7 and to test whether the subcellular localization of mutant ataxin-7 is important for the induction of Purkinje cell disease in vivo. To examine whether the same features found to be important for ataxin-7-induced Purkinje cell disease in aim 1 are critical for the ability of mutant ataxin-7 to induce disease in other neurons. To accomplish this, SCA7 transgenic mice with expression of ataxin-7 in photoreceptors, a neuronal cell type affected in SCA7, will be generated and characterized. Transgenic mice will also be developed to examine the ability of mutant ataxin-7 to induce disease in neurons throughout the brain. To gain insight into ataxin-7 function a series of experiments are proposed to characterize the cellular and subcellular expression of ataxin-7 and to identify proteins that interact with ataxin-7 using the yeast two-hybrid system.